A Novel Primary Cilium‐Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells

Abstract

Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co‐culture, conditioned media, human cancer spheroid, and organ‐on‐a‐chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF‐α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF‐β), which disrupts osteocyte cilia and IFT88 gene expression. This bi‐directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF‐β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell‐osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway.

Role of the osteocyte in bone metastasis – The importance of networking

“…The authors further postulated that histone H4, highly secreted by osteocytes in the conditioned medium, may also play a role, finding upregulation of tumour suppressors TNF-related apoptosis-inducing ligand (TRAIL), p53, LIM domain and actin-binding protein 1 (LIMA1) and desmoplakin (DSP), as well as down regulation of oncogenic promoters (CXCL1 and CXCL5). Taken together with the previously discussed findings of a suppression role for osteocytes [28] , this study points to conditioned media–based therapy as a viable option in the treatment of breast cancer metastases. Further exploration is required in other cancers, as work in our lab has indicated suppression signalling may be shared across cancer types [28] .…”

“…Taken together with the previously discussed findings of a suppression role for osteocytes [28] , this study points to conditioned media–based therapy as a viable option in the treatment of breast cancer metastases. Further exploration is required in other cancers, as work in our lab has indicated suppression signalling may be shared across cancer types [28] .…”

“…Additional in vitro organ-on-a-chip studies from our group applied selective mechanical stimulation of just osteocyte cells in co-culture, without stimulating cancer cells, also investigated breast cancer cell-osteocyte crosstalk, finding that shear loading of osteocytes can actually increase breast and prostate cancer cell invasion [22] . In a further study, we found that conditioned media from multiple breast and prostate cancer cell lines can reduce osteocyte mechano-sensitivity to fluid shear stress, as measured by cyclooxygenase-2 (COX-2) expression, an early mechano-transduction messenger [28] .…”

“…In a parallel with the vicious cycle paradigms traditionally associated with osteoblast and osteoclast cells, recent work from our group has identified a potential feedback loop between osteocytes and cancer cells [28] . In a series of conditioned media, cancer spheroid and organ-on-a-chip experiments, we found that tumour necrosis factor alpha (TNF-α) is secreted by osteocytes, which in early metastasis vastly outnumber cancer cells, suppressing proliferation of breast and prostate cancer cells, while encouraging migration.…”

“…This disruption of the cilia/IFT88 expression blocks TNF-α secretion from osteocytes, thereby switching off both the inhibition of cancer cell proliferation and the up-regulation of migration. Hence, increased numbers of cancer cells produce more TGF-β, further disabling osteocyte TNF-α secretion in a positive feedback loop reducing cancer cell migration and increasing proliferation, thereby accelerating metastatic tumour growth [28] . Most interestingly, this osteocyte suppression mechanism was found to be shared to varying degrees between breast and prostate cancer cells, indicating that further exploration could identify broad-based anti-metastatic treatments.…”